Glucocorticoids have a number of diverse effects in different body tissues. Glucocorticoids, in topical, oral and inhaled formulations, are useful for their anti-inflammatory and immunosuppressive properties. Several glucocorticoids such as budesonide and ciclesonide are used for treatment of several disorders.
The synthesis and purification of glucocorticoids have been disclosed at different instances. However, most of these synthetic procedures involve toxic solvents or long reaction times and are ineffective for large scale synthesis. For instance, U.S. Pat. No. 3,929,768 discloses a process for preparation of budesonide by reacting 16, 17-dihydroxy compound with aldehyde in solvents such as dioxane, methylene chloride or their combinations.
DE 4129535 discloses a process for the synthesis of Ciclesonide which involves the intermediate 16A, 17-[(R,S)-cyclohexylmethylenedioxy]-1 13, 21-dihydroxy-pregna-1 4-dien-3,20-one which is obtained by an acid catalysed reaction of 11β, 16α, 17, 21-tetra hydroxypregna-1,4-dien-3,20-one with cyclohexane aldehyde.
WO 02/38584 discloses the synthesis of Ciclesonide by reacting corresponding 16, 17-ketals with a cyclohexane aldehyde in the presence of 70% perchloric acid, 1-nitropropane as solvent. However, perchloric acid is a dangerous solvent and can cause serious accidents with fatal consequences.
U.S. Pat. No. 6,169,178 relates to a process for the preparation of budesonide and of 16, 17-acetals of pregnane derivatives structurally co-related thereto comprising treating 16, 17-dios or of 16, 17-ketals or cyclic acetals with aldehydes in the presence of aqueous hydrobromic acid or hydroiodic acid used as reaction catalyst or solvents. However, hydroiodic and other hydrohalic solvents are corrosive, light sensitive and expensive. Further, these acids also post environmental problems. Notwithstanding the use of hydrohalo acids requires use of special equipment since they are extremely corrosive and consequently increase the cost of production.
U.S. Pat. No. 5,556,964 discloses a process for the preparation of budesonide by reacting 16α-Hydroxy Prednisolone in acetonitrile in the presence of p-toluene sulfonic acid as a catalyst. There are certain other patents that use alkyl sulfonic acid instead of aryl sulfonic acid for the synthesis of budesonide or similar compounds. However, sulfonic acids are hazardous solvents and FDA has expressed significant concern over the presence or traces of sulfonic acid in pharmaceutical products. Hence, there is a need to have a process for the synthesis 16, 17-acetals of pregnane compounds that is industrially scalable and which does not involve the use of harmful solvents.